Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCA218

Poster Communications

Metformin treatment in pregnant mice alters expression of genes involved in de novo lipogenesis and β-oxidation in fetal livers

A. Rollings1, K. Lovell1, H. Thomas1, C. Byrne1, F. R. Cagampang1

1. University of Southampton, Southampton, United Kingdom.


Introduction: Prevalence of maternal obesity during pregnancy is on the rise, and may contribute to increased offspring susceptibility to non-alcoholic fatty liver disease (NAFLD) in adulthood. Metformin (MET) is now being prescribed to treat gestational diabetes but may also impact on future NAFLD risk in the offspring. Our previous study in mice shows that maternal MET treatment during pregnancy can either offer protection or further increase offspring susceptibility against NAFLD depending on maternal body condition during pregnancy. However, it is still unknown if maternal MET treatment is already priming the fetal liver to future NAFLD risk. Aims: To examine the effects of MET treatment in lean and obese pregnant mice on expression of genes involved in de novo lipogenesis, β-oxidation and inflammation in the fetal livers. Methods: Female C57/BL6J mice were fed a control (C, 7% kcal fat) or an obesogenic high fat (HF, 45% kcal fat) diet six weeks prior to conception and during pregnancy, with half of C and HF dams given metformin in drinking water (250mg/kg bodyweight/day) throughout pregnancy. This generated four dam groups: C (n=6), C+MET (n=6), HF (n=6), HF+MET (n=13). Dams were killed on day 16 of pregnancy and fetal livers taken for gene expression analysis. Expression of genes involved in de novo lipogenesis (ACLY, ACC, FASN), β-oxidation (CPT-1) and inflammation (CCL, TLR2) were assessed by real-time RT-PCR. Data was analysed by two-way ANOVA to determine effects of maternal diet and metformin. Results: In the non-MET groups, HF diet-induced maternal obesity reduced fetal hepatic ACC mRNA levels vs levels in fetuses from lean C-fed dams (0.70-fold p<0.05). Hepatic mRNA levels of ACLY, FASN, CPT-1, CCL and TLR2 were similar in fetuses from both C and HF dams. On the other hand, MET treatment to lean C-fed and obese HF-fed pregnant dams reduced fetal hepatic FASN mRNA levels vs those in fetuses from untreated lean (C+MET vs C, 0.36-fold p<0.001) and obese (HF+MET vs HF, 0.42-fold p<0.01) dams, respectively. Maternal MET treatment also reduced hepatic mRNA levels for ACLY (0.64-fold p<0.05) and CPT-1 (0.36-fold p<0.01) but only in fetuses from C dams. Maternal MET had no effect on hepatic CCL and TLR2 mRNA levels in fetuses from either lean C-fed or obese HF-fed dams. Conclusion: Maternal obesity did not bring about marked changes on expression of gene involved in de novo lipogenesis, β-oxidation and inflammation in the fetal liver. However, MET treatment to pregnant mothers resulted in significant alteration in expression levels of these genes in the fetal liver. These changes in gene expression during fetal development may contribute to the priming of the offspring liver, and may have long term consequences on disease susceptibility of the offspring in later life.

Where applicable, experiments conform with Society ethical requirements